The skin plays multiple roles in protection from environmental insults. Environmental exposure results in the progressive deterioration of skin that is initially cosmetic but can lead to end stage diseases such as actinic keratosis and skin cancer. Hereinafter, while the skin will be discussed specifically, it is to be understood that the remarks are applicable to organs and tissues in general.
Health of skin, as well as other tissues and organs, is dependent upon supplies of many essential nutrients to cellular components which are a part thereof, oxygen in particular, as well as the efficient removal of waste products such as carbon dioxide, and other metabolic end products. An optimal supply of oxygen is required in order to support metabolic pathways which inter alia, support the cellular mechanisms that lead to resistance of skin deterioration.
The delivery of oxygen to skin via blood circulation is distal to delivery to most other organs. Further, the uppermost living layer of skin, i.e., the “epidermis,” is non-vascular. This leaves the upper layers of skin at high risk of receiving insufficient oxygen.
Skin is a complex organ system, consisting of multiple layers. The uppermost, or “stratum corneum” layer, consists of non-living material derived primarily from the terminal differentiation of epidermal keratinocytes, and provides a protective barrier for the underlying components of skin. The epidermis contains a number of cell types, although keratinocytes are the major cell type. Dermal fibroblasts are embedded within a matrix comprised of collagen, elastin, proteoglycans, and other extracellular matrix molecules. Blood capillaries are found in the dermis, but the epidermis is non-vascular.
As people age, progressively deleterious changes in skin appearance occur. The initial changes are the loss of smooth skin texture and the appearance of age spots, followed by changes in elasticity that lead to the appearance of skin wrinkles. The age at which these changes appear and the rate at which one stage progresses to the next varies greatly from individual to individual. During the normal aging process, both the epidermis and dermis become thinner with a loss of cell numbers and connective tissue, leading to the appearance of fine wrinkles. Ultraviolet (UV) irradiation from the sun causes photodamage that accelerates skin deterioration. In contrast to the thinning observed in sun-protected skin, photodamaged skin has a thickened and rough appearance with an increase in deeper skin wrinkling which occurs in dermal tissue. Photodamage also causes end-stage skin deterioration including pre-malignant lesions termed actinic keratosis and skin cancer.
Compelling evidence now indicates that oxidative stress, defined as an abnormal accumulation of reactive oxygen species (ROS hereafter) is involved in the pathophysiology of skin deterioration. ROS include, inter alia, superoxides, the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite, and hypochlorite. See, e.g., Simonian, et al., Ann. Rev. Pharmacol. Toxicol. 36:83-106 (1996), incorporated by reference. All cells are exposed to ROS during the normal course of energy metabolism, via environmental exposure and/or immune surveillance. While ROS are involved in normal cell signaling pathways, elevation of ROS during oxidative stress disrupts signaling pathways, often resulting in cell death by apoptosis or necrosis. Thus, it is likely that ROS are involved in the decrease in cell number observed over time, even in sun-protected skin.
Exposure to the ultraviolet rays of sunlight is a major source of skin oxidative stress. Two major targets for damage by ROS in skin are DNA and protein. DNA damage is of particular interest in that unrepaired damage can lead to the loss of skin cells and to altered functioning of cells that survive genotoxic stress.
While some changes in skin during aging can not be avoided, much skin deterioration at an early age is avoidable. Skin cells contain a number of protective mechanisms for the prevention and repair of ROS damage to DNA and protein. For example, a number of intracellular molecules, including glutathione and the antioxidant vitamins C and E play key roles in scavenging ROS before they can react with cellular macromolecules. Indeed, the antioxidant vitamins have already found application in the prevention of skin deterioration, as they are components of many skin creams. Also, cells contain complex mechanisms for the maintenance of genomic integrity. Of particular interest herein is the accumulating evidence for the involvement of DNA repair mechanisms in maintaining the genomic integrity of organs and tissues subjected to genotoxic stress caused by, e.g., ROS, including skin.
The delivery of oxygen is important for proper maintenance of cell energy metabolic pathways, which in turn is important for alleviating the problems discussed herein. It is desirable to have a method available by which oxygen delivery to a tissue or organ, such as the skin, can be improved. Hence, one object of the invention is a method for improving delivery of oxygen to tissues and organs, such as skin. Yet a further aspect of the invention are compositions useful in achieving this goal. Still a further aspect of the invention is the treatment of conditions where improved oxygenation is called for, via application of the methods and compositions of the invention.
How these aspects of the invention are met will be seen from the disclosure which follows.